Pain is described as a complex constellation of unpleasant sensory, emotional and cognitive experiences provoked by real or perceived tissue damage and is manifested by certain autonomic, psychological and behavioral reactions and is a disease of epidemic proportions. From a neurobiological perspective, pain is believed to be of three different aspects: first, pain that is an early warning physiological protective system, essential to detect and minimize contact with damaging or noxious stimuli and is called ‘nociceptive pain’; second, pain that is adaptive and protective, by heightening sensory sensitivity after unavoidable tissue damage, which is mainly caused by activation of the immune system by tissue injury or infection and is normally called ‘inflammatory pain’; and the third type is pain which is not protective, but maladaptive resulting from abnormal functioning of the nervous system and generally called as ‘pathological pain’. This pathological pain is believed to be not a symptom of some disorder but rather a disease state of the nervous system, can occur after damage to the nervous system (neuropathic pain) or a situation where there is no such damage or inflammation (dysfunctional pain—like fibromyalgia, irritable bowel syndrome, temporomandibular joint disease, interstitial cystitis and other syndromes where there is substantial pain but no noxious stimulants and minimal/no peripheral inflammatory pathology).
Neuropathic pain is a pain caused by damage or disease that affects the somatosensory system. It may be associated with abnormal sensations called dysesthesia, and pain produced by normally non-painful stimuli (allodynia). Neuropathic pain may result from disorders of the peripheral nervous system or the central nervous system (brain and spinal cord). Thus, neuropathic pain may be divided into peripheral neuropathic pain, central neuropathic pain, or mixed (peripheral and central) neuropathic pain. Some treatment options for neuropathic pain include antidepressants (e.g. tricyclics and selective serotonin-norepinephrine reuptake inhibitors (SNRI's)), anticonvulsants (such as pregabalin, gabapentin, carbamazepine and oxcarbazepine and topical lidocaine. Opioid analgesics and tramadol are recognized as useful agents but are generally less recommended as first line treatments.
Analgesic agents include a group of drugs used to relieve pain and thus achieve analgesia. Analgesic drugs act in various ways on the peripheral and central nervous systems Analgesics include various drugs such as acetaminophen (also called paracetamol), non-steroidal anti-inflammatory drugs (NSAID) that inhibit mainly the enzyme cyclooxygenase (COX) and in turn reduce the synthesis of prostaglandins, adjuvant medications that help in reduction of pain such as serotonin-norepinephrine reuptake inhibitors (SNRI), selective serotonin reuptake inhibitors (SSRI), norepinephrine reuptake inhibitors (NERIs), tricyclic antidepressants, and the likes. Examples of analgesic agents include acetaminophen, aspirin, diflunisal, ibuprofen, naproxen, fenoprofen, fenbuten, flurbiprofen, indoprofen, ketoprofen, indomethacin, ketorolac, diclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, mefenamic acid, tolfenamic acid, meclofenamic acid, tolfenamic acid, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, nimesulide, licofenole, phenylbutazone, oxphenbutazone, antipyrine, aminopyrine, thiocolchicoside, duloxetine, milnacipran, amitriptylene, desipramine, imipramine, bupropion, lefetamine, methylphenidate, pregabalin, paroxetine, citalopram, clonidine, guanfacine, tizaidine morphine, oxycodone, hydromorphone, hydrocodone and the like or salts thereof.
Acetaminophen extended release tablet (TYLENOL® marketed by McNeil Cons) is indicated for management of mild to moderate pain, moderate to severe pain with adjunctive opioid analgesics and reduction of fever.
Ibuprofen is available as oral tablet (300 mg, 400 mg, 600 mg and 800 mg) and suspension (100 mg/5 mL) and used for the management of mild to moderate pain, and for management of moderate to severe pain as an adjunct to opioid analgesics.
Naproxen is available in the form of naproxen base (NAPROSYN® tablets as 250 mg, 375 mg and 500 mg; EC-NAPROSYN® delayed-release tablets as 375 mg and 500 mg and as a suspension—125 mg/5 mL), and as sodium salt (ANAPROX® tablets as 225 mg and ANAPROX DS®—500 mg) and oral suspension form (NAPROSYN®. Naproxen is indicated for the relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and juvenile arthritis.
Diclofenac (VOLTAREN®-XR 100 mg extended-release tablets) is indicated for the relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis.
Meloxicam (MOBIC® tablet 7.5 mg or 15 mg) and a suspension (7.5 mg/5 mL). Meloxicam is approved for the relief of the signs and symptoms of osteoarthritis, arthritis and pauciarticular or polyarticular course Juvenile Rheumatoid Arthritis in patients 2 years of age and older.
Duloxetine hydrochloride (CYMBALTA® 20 mg, 30 mg and 60 mg capsules) for the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), for the management of neuropathic pain associated with diabetic peripheral neuropathy (DPNP), chronic musculoskeletal pain and fibromyalgia.
Pregabalin (LYRICA capsules of 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg; and a solution of 20 mg/mL) is indicated for management of neuropathic pain associated with diabetic peripheral neuropathy (DPN), post herpetic neuralgia, fibromyalgia, and in the treatment of partial onset seizures.
Gabapentin is available as NEURONTIN capsule (100 mg, 300 mg, or 400 mg), Neurontin tablet (600 mg or 800 mg); and Neurontin oral solution (250 mg of gabapentin per 5 mL) It is indicated for management of postherpetic neuralgia and in the treatment of partial onset seizures.
Thiocolchicoside is prescribed as a skeletal muscle relaxant, anti-inflammatory, analgesic and anesthetic at doses of 2 mg, 4 mg, 8 mg and 16 mg.
It is believed TRPA1 is expressed in nociceptive neurons. Nociceptive neurons of the nervous system sense the peripheral damage and transmit pain signals. TRPA1 receptor is activated by a number of irritants that cause pain, including allyl isothiocyanate (AITC) and allicin, the pungent ingredients in mustard and garlic extracts, respectively; as well as α,β-unsaturated aldehydes, such as acrolein. The TRPA1 channel is the primary molecular site through which the pain pathway gets activated through an unusual mechanism involving covalent modification of cysteine and lysine residues within the N-terminal cytoplasmic domain of the channel protein. Thus, TRPA1 modulators are highly implicated in the alleviation of pain.
PCT Application Publication Nos. viz., WO 2004/055054, WO 2005/089206, WO 2007/073505, WO 2008/0949099, WO 2009/089082, WO 2009/002933 WO 2009/158719, WO 2009/144548, WO 2010/004390, WO 2010/109287, WO 2010/109334, WO 2010/109329, WO 2010/109328, WO 2010/125469, WO 2010/004390, WO 2011/043954 and WO 2010/141805 describe various transient receptor potential (“TRP”) receptor modulators.
There still exists a need for easy to use and effective treatments for pain and further pain relieving compositions.